Steroid compounds



Patented Oct. 21, 1952 STEROID COMPOUNDS Paul E. Marla tt, Arthur R. Hanze, A Vern McIntosh, Jr;, and Robert H. Levin, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application September 15, 1951, Serial No. 246,864

6 Claims. (01. zen-239.57)

The present invention relates to a novel process for the preparation of certain steroid adducts, and to the novel products produced by the said process. This application is a continuation-inpart of our prior-filed applications Serial 187,364, filed September 28, 1950, now Patent No. 2,582,- 263, and 211,442, filed February 16, 1951.

The novel compounds of the present invention are 9-hydroxy-5,7-pregnadien-3,11,20-trione 5,8- maleic adduct Q-hydroxy lactones of the formula:

CH-COOR wherein R is hydrogen or a lower-alkyl radical, especially a lower-alkyl radical containing from one to eight carbon atoms, inclusive.

It is an object of the present invention to provide a novel group of compounds which are useful in the preparation of physiologically active steroid compounds containing an oxygen atom at carbon atom eleven. Another object of the invention is the provision of a process for the production of novel compounds, 9-hydroxy 5,7 pregnadien 3,11,20 trione 5,8- maleic adduct Q-hydroxy lactones. Other objects of the invention will be apparent to one skilled in the art to which this invention pertains.

The compounds of the present invention, as previously stated, are useful in the preparation of physiologically active steroid compounds having an oxygen atom attached to carbon atom eleven. Such compounds are of particular interest in the field of steroid research due to the biological activity of the cortical hormones and certain known derivatives thereof, which oxygenated steroids are known to have biological effects differing markedly from the unoxygenated steroids. It is, therefore, of importance to investigate the oxygenated derivatives of such adducts, as well as their transformation products. The importance of such investigation is moreover emphasized by the acute shortage of adrenal cortical hormones,

and the absence of any present suggestion for alleviation of the said shortage except through organic synthesis.

The compounds of the present invention are prepared by the oxidation of a starting 3,9,11- trihydroxy 5,7 pregnadien 20 one 5,8- maleic acid adduct Q-hydroxy lactone or 5,8- maleic acid monoalkyl ester adduct Q-hydroxy lactone to convert the hydroxy groups at carbon atoms 3 and 11 therein to ketonegroups. This is accomplished by mixing the starting adduct with chromic acid in the approximate proportion of about one mole of starting adduct to two moles of chromic acid. The chromic acid is advantageously added portionwiseto a glacial acetic acid solution of the adduct and this is preferably accomplished by dissolving approximately two molar proportions of chromium trioxide in a minimum amount of water, diluting the chromic acid solution with glacial acetic acid, and adding the glacial acetic acid solution of chromic acid to the glacial acetic acid solution of the starting adduct. Other modes of admixture are satisfactory, however, and will be apparent to one skilled in the art. The oxidation may be conducted by allowing the reactants to stand together at room temperature or below, or gentle heating may be applied if necessary, though with caution. Stirring of the reaction mixture may also be employed to advantage in some cases, to promote more intimate contact of reactants. A reaction period of one to five hours is usually satisfactory, although shorter or longer periods may sometimes be emp1oyed,,if desired. Upon completion of the reaction, excess chromium trioxide and/or chromic acid may be destroyed by addition of alcohol, the mixture of reaction products poured into an ice and water mixture, the water solution extracted With an organic solvent, e. g., methylene chloride, and the solvent solution worked up according to conventional procedure to obtain the desired triketone product. Alternatively, a two-phase system may be employed, by forming an aqueous solution of sodium dichromate and vigorously admixing this solution with a water-immiscible organic solvent solution, e. g., a benzene, toluene, chlorobenzene, chloroform, carbon tetrachloride, or like solvent solution, of the steroid adduct desired to be oxidized and working up the product according to conventional procedure. I

The starting 3,9,11-trihydroXy-5,7-pregnadien- 2Q-one 5,8-maleic adduct 9-hydroxy lactones are prepared by the lactonization of a 3,9,11-

- 3 trihydroxy-5,7-pregnadien-20-one maleic 5,8- adduct of the formula:

(EH3 i /\i on CH:

8aCH-C 0 on HO- men-o 0 on wherein R is hydrogen or a lower-alkyl radical, especially a lower-alkyl radical containing from one to eight carbon atoms, inclusive, by dehydrating the starting 3,9,11-trihydroxy adduct to cause splitting out of .one molecule of Water between the 8a-carboxy group. and the 9-hydroxy group with consequent production of a 9- hydroxy lactone. The dehydration may be effected 'by heating the starting adduct, preferably, though notnecessarily in an anhydrous organic solvent. As still a further method of effecting the dehydration, the starting adduct maybe-mixed with a lower-aliphatic alcohol, e. g., an alkanol such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, noctyl alcohol, or benzyl alcohol, or the like. The aforementioned substances, i. e., alcohols or anhydrides, apparently have sufiicient hydroscopicity to take up one molecule of water from the starting adduct, with consequent formation of the desireddactone, even though merely allowed to stand in admixturewith the starting adduct at room temperature or lower, without heating. Of course, 'it is usually preferred to employ heating-to effect the dehydration as this is the most simple procedure. The lactone of the maleic acid adduct may be esterified by conventional procedure, e.-g., by reaction with a dia zoalkane such as diazomethane, diazoethane, diazobutane, or the like, or even with employment of an excess of alcohol in the same reaction which is productive of the lactone from the 9-hydroxy maleic acid adduct. Thus, a 3,9,1l-trihydroxy maleic .acidadduct may be converted to a 3,11-dihydroxy lactone acid by heating, or to a 3,11-dihydroxy lactone acid ester by reaction with an excess of an anhydrous alcohol, such as those mentioned supra above for closing of the ring.

The 3,9,11-trihydroxy5,7-pregnadien-20-one maleie acid 5,8+adduc t is obtained froma 3,9,11- triacyloxy-5,7-pregnadien-20-one maleic anhydride adduct by careful saponification with about five'molar equivalents of a suitable alkali metal base and neutralization with an aqueous mineral acid, as more fully set out in U. S. application Serial 211,442, filed February 16, 1951, and the monalkyl esters thereof are obtained therefrom in conventional manner, as more fully disclosed hereinafter.

' These 3,9,11-triacyloxy-5,7-pregnadien-20-one adducts are obtained by acylation of a 3-hydroxy or 3-acyloxy-9,11-oxido-5,7-pregnadien- 20 one maleic adduct, as more fully set out in U."S. a'pplication Serial 187,364, filed September 28,1950. I

The 3- substituted-9,l1-oxido-5,7-pregnadien 20-one adducts are prepared by epoxidation of the 9,11 double bond of a 3 substituted- 5,7,9(I1)-pregnatrien-20-one adduct, as more 4 fully disclosed in U. S. application Serial 177,- 966, filed August 5, 1950.

The 3 substituted 5,7,9(1l) pregnatrien- 120-one adducts are conveniently prepared by the selective oxidation of a 22-enol ester of an adduct of 3-acyloxybisnor-5,7,9('11) -cholatrien- 22-als, as more fully disclosed in U. S. application Serial 121,224, filed October 13, 1949.

Adducts of 3,22-diacyloxybisnor-5,7,9(11),20- (22)-cholatetraenes [22-enol esters of 3-acyloxybisnor-5,7,9(11)-cholatrien-Z2-als] are conveniently prepared by subjecting an adduct of a 3-acyloxybisnor-5,7,9(1l)-cholatrien-22al to the actionof an acid an anhydride or an acid halide in the presence of an alkaline salt of the acid, as more fully disclosed in U. S. application Serial 111,974, filed August 23, 1949.

The starting adducts of 3-acyloxybisnor-5,7,- 9(1 1)-cholatrien-22-als can be prepared from adducts of 3-esters of dehydroergosterol by selective oxidation as more fully disclosed in U. S. application Serial 111,100, filed August 18, 1940.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

Preparation 1.Dimethyl maleate adduct of 3- beta acetoccy 9,11 oxido 5,7 -.pregnadie'n- 20-one' One gram (0.002 mole) of the I dimethyl maleate adduct of 3-beta-acetoxy-5,7,9(1l)- pregnatrien-ZO-one was dissolved in 25 milliliters of glacial acetic acid, and a solution of one milliliter of thirty percent hydrogen peroxide (four molar equivalents) in six milliliters of glacial acetic acid was added thereto at room temperature. The reaction mixture was heated on the steam bath for four hours and thereafter allowed to stand at room temperature overnight. The mixture was then poured into 300 milliters of water, the resulting precipitate separated by filtration, Washed with water, and dried. The yield was 810 milligrams of the oxido compound melting at 197206 degrees centigrade. After five recrystallizations from methanol and acetone-hexane, the dimethyl maleate adduct of 3-beta-acetoxy-9,1l-oxido- 5,7-pregnadien-20-one melted at 216-221 degrees centigrade, [alpha] D +1L4 degrees (chloroform).

Analysis:

Calculated Per cent C, 67.68;v Percent H, 7.44 Found: Per cent 0, 67.74; Per cent H, 7.35

beta acetoaty 9,11 oxido 5,7 pregnqdien- 20-one Five grams (0.011 mole) of the maleic anhydride adduct of 3-betaacetoxy-5,7 ,9(11) poured into'about one liter of water, the resulting precipitate separated by filtration, Washed with water, and dried in a vacuum desiccator. The

7. Preparation 2.Maleic anhydrzde adduct of '3} yield was 4.88 grams (94.8 percent), melting at 232-246 degrees centigrade. After two recrystallizations from acetone, crystals of the maleic anhydride adduct of 3-beta-acetoxy-9,1l-oxido- 5,7-pregnadien-20-one, melting at 240-246'degrees centigrade. were obtained.

Analysis Calculated: percent C, 69.21; per cent H, 6.89 Found: per cent C, 69.43; per cent H, 6.94 69.30; 6.97

Preparation 3.-Maleic anhydride adduct of 3- beta cemetery-9,11-0xido-5J-pregnadien-20- one A solution of fifty grams of the maleic anhydride adduct of 3-beta-acetoxy-5,7, 9(11)-pregnatrien-ZO-one in 1200 milliliters. of glacial acetic acidwas prepared by heating the ingredients togetheron, a steam bath. Themixture was then cooled below forty degrees centigradegand fifty milliliters of thirty percentv hydrogen peroxide in 300 milliliters of glacial acetic acid added thereto. The mixture was then heated on the steam hathv for one. hour at a temperature. of 85 degrees centigrade or above, and'was then poured into three to five volumes of ice and water. The yield was 47.7 grams (92 percent), melting degrees (chloroform). The product was dissolved inmethylene chloride and precipitated by addition of ether to. give 37.7 gramsof purified prodnot having a melting point of 254 to 259 degrees centigrade, Ealphal5 +332 degrees (chloroform)- Y Preparation 4 In the same. manner as given. abovefor the preparation of 3-beta-acetoxy-9,l1-oxido.-5,7- pregnadien-ZO-one, maleic anhydride. adduct, the following compounds were prepared; r

('1) Maleic anhydrideadduct of 3-benzoyloxy- 9,11-oxido-5,7-pregnadienr-one, M. P. 258-260 degrees centigrade, [alphalpi-l-MA degrees (chloroform) Analysis:

Calculated: per cent C, 72.43; per cent H, 6.46 Found:

' point 238-243 degrees centigrade, [alpha] +3l.1

per cent C, 72.62; per cent H, 6.42 6.38

(2) Maleic anhydride adductof 3-heptanoyloxy-9,1l-oxido-5,7-pregnadien-20-one, M. P. 168- 1695 degrees centigrade, [alphal -l-261 degrees (chloroform) Analysis:

Calculated: per cent C, 71.48; per cent H, 7.69

Found: per cent C, 71.27; per cent H, 7.43- 7144'; 7.65

a yield of'19.4 grams of desired B-beta-hydroxy- 9,11-oxido-5.,7-pregnadien-20-one maleic acid adduct, melting at 229-233 degrees centigrade with decomposition, was obtained. I An additional crop of crystals was obtained by concentration of themother liquor.

Preparation 'a-Mazeic anhydrz'de adduct of 3-beta-hydroxy-9J1 -omido- 5,7-pz'egnadiem-Z 0.- 017 6 one maleic acid adduct (19.4 grams) "was placed in a vacuum oven and'heated for ten hours at 137-140 degrees centigrade under a pressure of only one-half millimeter of mercury. The yield of desired anhydride, which melts at 233 to 240 degrees centigrade with decomposition, was quantitative.

Preparation 7.-Monomethyl maleate of .i-Det'asodium chloride, and dried over sodium sulfate.

The yield was 4.93 grams, melting point 130-160 degrees centigrade. After recrystallization three times from a solution of chloroform, methanol, and ether, the melting point was 193-198 degrees centigrade, [alpha] +19.4 degrees (chloroform).

Analysis: 1

Calculated: Percent O, 68.10; percent H, 7.47; percent OGHJ, 6.75 Found: vPercent C, g77;3 (7) ;percent H, percent 0011:,

Preparation 8.-Dimethyl maleate of- 3-beta-hy- (hoary-9,1 1 mantle-5,7 -pregnadien-.20-one A suspension of 0.65 gram of the monomethyl ester of the maleic acid adduct of 3-betahydroxy-9,l1-oxido 5,7 pregnadien-ZO-one in twenty milliliters of anhydrous ether was treated with an excess of diazomethane in methylene chloride solution. On addition of methylene chloride the compound went into solution and was allowed to stand about two hours, the solution evaporated to dryness, and the residue dissolved in twelve milliliters of hot ethanol, filtered.

Preparation 5.Mal eic' acid adduct of 3-betahydromy-9,11 -0zm'do-5 ,7 -pregna.dien-20-one Approximately 445 milliliters of five percent.

sodium hydroxide solution was added to 22.26 grams of 3-beta-acetoxy-9,lloxido-5,7-pregnadien-20-one maleic anhydride adduct in a oneliter Erlenmeyer flask, and the mixture stirred until the solid had gone. into solution. About 185 milliliters often percent hydrochloric acid was then added at room temperature or below. until the mixture was acid to Congro red paper, whereupon the hydroxy diacid began to precipitater Upon cooling the flask overnight, filtering and air-drying the product atroom temperature,

concentrated, water added, and the solution placed in the refrigerator. The precipitate was separated by filtration to give a yield of 0.54 gram, melting at 207-211 degrees centigrade. The product was passed over a column of alumina for purification, and this procedure yielded 0.50 gram of product, which upon crystallization from methanol hada melting point of 210-212 degrees centigrade,

} ['alpha] +15.4 degrees (chloroform) Analysis;

Calculated: Percent: C, 68.62; percent 'H, 7.68; percent 0013251313 Found: Percent C, 68.62; percent H, 7.61; percent 0011;, 12.10 63.61; 7. 6 l2l22 Infra red analysis was in agreement withthe structure proposed.

7 8 Preparation 9.3,9,'11'-tricaeto:cy '-5;7 preg- Preparation 13'.'-3- ac'etomy 9,11 -diprogiiownazdien-ZO-one malete anhydride add'uct' ozcy-;7-pregnadien-2c one mal'ez'c anhydride Toa'one-liter three-neck round-bottom flask addud Y .equipped with stirrer and thermometer, immersed In exactly t same manner as giveni'n Prepain an ice-salt bath, were added eight rams of ration 9, this compound is prepared-froma-ace 3 beta acetoxy 9,11 oxido 5,7 pregn'adient xy 9,11 ide 5,7 pregnadien 2o one 1 1 1 anhydrideadduct d maleic anhydride adduct using an excess-of proii' 0f a t y r e (Merck reagent gra picnic. anhydride and stannic chloride catalyst. After solution was complete and after the inside i temperature had dropped to between zero and Preparation 14.-'-'3,9,11 trihydroxy 5,7 pregfour d rees c nti r d Sixteen drops o wnadien-ZO-orzamaleic acid adduct disodium salt drous stannic chloride was added thereto. he

--The maleicanhydride adductof' 3-.beta,9,'-11- reaction: was allowedto contmue for 45 minutes triacetoxy 5,7 pregnadien one (1105 grams) l ii tii ffifiitui e wel $555 inifi ifilie iiii'is i 15 a Y Q milliliters P ee ice and water. The ice and water mixture was p q 't 5911191911 a q l w 1.1131117 stirred until all of the acetic anhydridehad hy- T "P T m a -wq mh mifl wm drolyzed and the product had precipitated as i .1 tem eratu P n F di u d white platelets. The white product was filtered 2O W FE ea. FF QiR Q Fi fi ,m liitFs i Wt??? off .and dried. The Weight was 9.42 grams, M. P. m m ?P "3 9. 393 4. .s 9 205-215 degreescentigrade. Two recry stallizas wm hydroxide? was. ewq c i n tions from ace'tone-isopropyl ether mixture gave a r pmie i WQ h f 947-1511931161 4;2- jgrams,-..M. P. 228-234 degrees Centigrade cfwhich time f r a p w 9Jl ql QX5fr -(tube),-265"-2'70 degrees centigrade with softening 7 d -Qn ;.me 39 d dq f f 1 at 235. degrees centigrade (block); [alphal d sa t w o p ete Use o P0 a llm..hy 84.7 degrees; (chloroform). The yield was 43 de in place of i m h rox e. i roi s percent. i tive of the dipotassiurn' saltj I v a a s 1 i I Preparation 1 5.'3,9,11 ltrihyidromye5j se s.

- Found: C, 65.26; H, 6.72

,- i 65.26; 6.72 The reaction'mixture from Preparation '14 was v partially neutralized-by addition of l00 milliliters Preparation 10 3 bg'nzoylomy 9 11' m of three normal hydrochloric acid and then evap toxy; 5,7 pregnadien g mamanhydflde orated in vacuo at forty degrees centigrade' to a adductvolume of 310 milliliters, 2 thereby removing all 1 dioxane. The reaction mixture was then made e a y e s m mnner as glven m Prepa' acid to" C rise r paper by .eddih'g eighty milliratwnfi. i m o d 15 P r from -m liters off'three: 'lldrll'ial hydrochloric acid h'd' zoylqxy 'T'x pregnaqien 20 one 40 placed in the refrigeratorfor several hours. "The maleic anhydride adduct (Preparation 4). yi e1 d of crud rd duct a sbffih This a red s infan 's. eminds oifafano w p odium hydroxide',' .diluted to' 2 0 0 milliliters with 32 &2 g 20 one male water, made acid with milliliters of one normal n e a 45 hydrochloric acid, and cooled. The yield was 5.62 'In exactly the same manner 'as given in Prepa grams of white needles, M. P. 255-264. degrees ration-9, this' compound is prepared from 3-hepcentig'rade. x i

Preparation, 11 .--3 heptanoyloxy 7 9,11 diace- Preparation. V :9 hydrang- 5,7-pregnadien-20-'one 5,8-maleic acid adduct 9-hydroxylactone I i v i v 2 I i on 'ee 1etieii' CHa/ o v i i lactonipation I r cH-oooH i (DH-COOK t hb mg 9,11 oxid 5,7 pregnadien 20- 3,9,11trihydroxy-5,7 pregnadien-20-one 58 ne aleic anhydride adduct (Preparation 4) maleic acid adduct was dissolved in twenty milli-v liters; of acetic anhydride and one drop of dry" Preparation 12.-3,9,11 triacetory 5,7 preg- Pyrldme added as catalyst. The 'solution' nadien ZO-O-ne dimethyl malgate adduct Was-allowed to stand at room temperature. for.

. v v fifteeni hours. 4 In-the process of isolation the --In exactly the same manner as given in Prepaproduct'was taken to dryness 'under vacuum at ration 9, this compound is prepared from 3-acesteam bath temperature (eighty degrees -centi.- toxy 9,11 oxido 5,7 pregnadien' 20 one grade) and redissolved 'in'an organic-solvent.

dimethyl maleate adduct (Preparation ,1).- From this solvent an amorphous solid'was' obtained. infrared studies on this material established the structure as that of 3,ll-diace'toiiy- Q-hydrbxy-fi.7-pregnadien 20 one 5,8 maleic acid adduct 9-hydroxy lactone.

Preparation dz-3,941 mt diary 5,? prey o'o'H H561) on 3,9,11 trihydroxy 5,7 -pregnadlen 20wne 5-,8-

maleic. acid adductl-from Preparation 15') was dissolved; in twenty milliliters-of anhydrous diethyl ether and the mixture heated at, about reflux temperature. (35 degrees centigrade) for a period of about two hours Excess ether was then removed hyevaporatiorr and remaining solvent taken oii under vacuum, leaying awhite sol-id identifi'ed by infrared spectrum as'j 3, 9, we t 'f 'k r e r fii -one melee acid 'adduct 9-hydroxy lactone flhestructure of this solid was proved aee yatmn with acetyl chloride to give 3,1ljmacetoxy-ll' liydroiiy- 5,7-pregnadien-z' one, 5,8 maleiciacid addiict 9-hydroxy laetone, which had an infrared s ec"- trum identical with that produced by the sarii compound obtained in the manner 01" Preparationlfi.

This compound, -3,9,1i-trmydroxy-a'f-pregdroxy lactone, can also be converted hypo ri ventional procedure to esters thereof by esterifi cation at the carboxy group using aidiazdalka'ne, e. g., diazomethane, diazoethane, diazopro ane, dizaizolmt'ane,v or in other conventional manner, such as with an alcohol, e. g., methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, amyl alcoho, hexyl alcohol, heptyl alcohol, octyl alcohol, benzyl alcohol, or the like.

Preparation 18.-'3,9 ,1 1 trihydroxy' 5,7 pregnadien-ZO-one 5,8 -maleic acid monomethyl ester adduct 9-hydroxy lactane To a solution of 319111mnn aroxwsxi pree grams, moimole) m co mniiiiter or metnfanqli immersed in an ice-liath, added portion wise 'over a" period of one iiair haul- 3516f mul liters (an excess) of a methylene chloridesolu-'- tion of diazomethaneg- The? reaction was allowed to Stand liv'rliighfi' a't room temperature ...n 10 and excess diazomethane'then boiled off on a steam bath under the hood. The remaining solvent was then taken off, under vacuum, leaving 6,2'7 gramsof a white solid, the infrared spectrum of which indicated it to be. the desired 3,9,11-trihydroxy-5,7-pregnadien 20 one 5,8-maleic acid monomethyl ester adduct 'Q-hy dr'oxy lactone.

The dehydration may be accomplished in the 1 y same manner, by empmymem o'f'other amen -1s,

such as' ethyl alcohol, propyl alcohol, isoproii'yl alcohol, butyl alcohol, pentyl alcohol, hexyl al cohol, heptyl alcohol, octyl' alcohol, or benzyl alcohol, and the like, instead of methyl alcohol. Likewise, other esterifying agents such as diazoethane, diazopropane, diazobutane, diazooctane,

and the like may be employed as esterifying agents, or, alternatively, the starting 3,9,1 1-tr'ih'ydroxy acid may mere1 be heated together with the desired alcohol, such as those mentioned above, to effect both esterification and lactonization.

Example 1. 9-hydroxy-5,7-pregnadien-3,11,20-

trione 5,8-maleic acid adduct 9-hydroxy Zactone 40 3,9,1l-trihydroxy-5,f7 pregnadien-20eone 5,8-

maleic acid adduct (50;) milligrams, 0.091 mole):

was; dissolved in twenty milliliters of glacial acetic acid and to this solution was added a s o lution of chromic oxide g220 milligrams 0.0022

- mole) dissolved in five; drops of water and; (11 luted with twenty milliliters of glacial acetic acid.

The solution wasallowedto stand at room.- tempe llr for a .f -h r .periq a ;,the e ess i chromic oxide then destroyedwith,fifteen"millisoliters of ethanol. Thereaction mixturenwa s poured intoice' and water and'the water m;

tion extracted three times with 200-mi1lilite'r portions of methylene chloride.

was removed under vacuum and the resulting soliddried under vacuum at steam-bath, temperature ('eightydegi'es' centigrade). The product was taken up in 0.5 normal sodium hydroxide .solution and acidified to Congo red paper with 1 The solvent ester of the lactone in pure form. Recrystalliza- 7 tion from methanol gave an analytical sample:

In like manner,-by oxidation ofother starting 5,8- ma1eic acid monoalkyl ester adduct Q-hy;

droxy lactones, such as the 9-hydroxylactones of 3,9,11-trihydroxy-5,7-pregnadiemone 5,8

maleic acid monoethyl, monopropyl, monoisopropyl, monobutyl, monopentyl," menohexyl, monoheptyl, monooctyl, monobenzyl," or like monoalkyl ester adducts, are prepared the corresponding 9-hydroxy 5,7 pregnadien 3,11,20- trione 5,8-maleic acid monoalkyl ester adduct 9- Analysis:

galcuatedz 0 percent, 68.70; H percent, 6.65: CHsOpereent, 6.82

oun

Example 2. iI-hydFory-5,7-preenadien 3 ,1 1 ,2 0

trione,5,8-maleic acid monomethyl ester adduct 9-hydroxyulactone CH; CH:

CH-COOMe CH I 2 c=o r cn-oooMe To afsolution of 3,9,11-trihydroxy-5,7-pregnadien-20-one 5,8-maleic acid monomethyl ester adduct 9-hydroxy lactone (Preparation 18) (6.27 grams, 0.0137 mole) in 300 milliliters of glacial acetic acid, was added a solution of chromium trioxide (2 .6 -grams,'-0.026 mole) in a minimum amount of water and diluated with seventy mil-' liliters of glacial-acetic acid. The oxidation reactants were allowed'tofstand; atroom t'emperature for three hours," at the end of which time 100'milliliters of absolute alcohol was added C percent, 68.62: H percent: 6. 51: 01130 percent, 6. 84

hydroxy lactones, such as 9-hydroxy-5,7-pregnadien-3,11,20-trione 5,8-maleic acid monoethyl ester adduct 9-hydroxy lactone, 9-hydroxy-5,7-

pregnadien-3,11,20-trione 5,8-maleic acid monopropyl ester adduct 9-hydroxy lacetone, 9-hydroxy-5,7-pregnadien-3,11,20 trione 5,8 maleic acid monoisopropyl ester adduct 9-hydroxy lactone, 9'-hydroxy-5,7-'pregnadien 3,11,20 trione 5,8 maleic acid monobutyl ester adduct 9 hydroxy lactone, Q-hydroxy-5,7-pregnadien-3,11,20- I trione 5,8-maleic acid mon'oamyl ester adduct 9- hydroxy lactone, 9-hydroxy-5,7-pregnadien-3j-11," 20-trione 5,8 maleic acid monohexyl esteradduct 9-hydroxy lactone; Q-hydrOxy-BR-pregnadien- 3,11,20-trione"5,8-maleic acid monoheptyl ester to eliminate excess chromium trioxide. After standing 'an additional twenty minutes, the rea'ction mixture waspoured'into four liters of ice and water. The water was extracted three times with 500-milli1iter portions of methylene chloride.-

The methylene chloride solution was washed with saturated sodium bicarbonate solution and then with water until the washings were neutral to P-hydrion paper. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent taken off under vacuum leaving grams of a white solid.

This solid was taken up in '75 milliliters of methylene chloride and milliliters of methanol,

added. The solution was then concentrated until prisms began separating from the boiling solution. After cooling the solution to room temperature and allowing it to stand for several hours, 3.46 grams of white prisms were collected, M. P. 285-290 degrees eentigrade (block). Further concentration gave a second crop, 1.46 grams, M. P. 288-290 degrees centigrade. I The total'yield was 4.92 grams. f p

Analysis: I

Calculated: 0 percent, 68.70; H percent, 6.65

, Found: C percent, 68.62: H percent, 6.51 8.72;

ialphaln +1ll- (chloroform) I adduct 9-hydroxy lactone, 9'-hydroxy-5,7"--pregnadien-3,l1,20-trione'5,8 maleic acid monooctyl ester adduct 'Q-hydroxy lactone, Q-hydroxy-Sflpregnadierieil1,20-trione 5,8-maleic acid mono benzylester adduct Q-hydroxy lactone, andfth'e like.

It is tobe understood that the invention 'isnet to be limited to the exact details of operation or exact compounds shown and described, as obvious modificationsand equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the ap, pended claims. v l t Weclaim:

v1. 'A 9 hydroxy-5,'I-pregnadien-3,11,2(fitrione 5,8-maleie adduct Q-hydroxy lactone 'of the formula:

wherein R is selected from the group consisting of vhydrogen and a lower-alkyl group containing from one to eight carbon atoms, inclusive.

2. 9 hydroxy-5,7-pregnadien 3,11,20 trione 5,8-ma1eic acid adduct 9-hydroxy lactone,

3. 9 hydrOXy-Q'Z-pregnadien 3,11,20 trione 5,8-ma1eic acid monomethyl ester adduct 9,-hy droxy lactone.

A. The process which; comprises: oxidizing a starting 3,9,11-trihydroxy+5;7,-pregnadien-20-one 5,8-ma1eic adduct Q-hydroxy lactone of the for- 1 mula:

il H H0 2 GH-COOR wherein R is selected from the group consisting of hydrogen and a lower-alkyl group by mixing a solution of approximately two moles of chromic No references cited. 

1. A 9-HYDROXY-5,7-PREGNADIEN-3,11,20-TRIONE 5,8-MALEIC ADDUCT 9-HYDROXY LACTONE OF THE FORMULA: 